MXPA06004244A

MXPA06004244A - Muscarinic acetycholine receptor antagonists.

Info

Publication number: MXPA06004244A
Application number: MXPA06004244A
Authority: MX
Inventors: Hongxing Yan
Original assignee: Glaxo Group Ltd
Priority date: 2003-10-14
Filing date: 2004-10-12
Publication date: 2006-06-28
Also published as: AU2004281724A1; US20070105895A1; ES2358673T3; JP2007508390A; KR20080067023A; EA013435B1; ATE494285T1; DK1677795T3; WO2005037280A1; UA87473C2; JP4796552B2; EP1677795A4; TWI409060B; TW200811171A; EA200702617A1; IL174843A0; AP2006003566A0; HRP20110232T1; US20070238752A1; CA2542657A1

Abstract

Muscarinic Acetylcholine Receptor Antagonists and methods of using them are provided.

Description

ANTAGONISTS OF THE ACETILCOLINE USCARINIC RECEIVER FIELD OF THE INVENTION This invention relates to novel derivatives of 8-azoniabicicio [3,2,1] octanes, pharmaceutical compositions, processes for their preparation and their use in the treatment of diseases mediated by the muscarinic receptor of acetylcholine M3.

BACKGROUND OF THE INVENTION Acetylcholine released from cholinergic neurons in the peripheral and central nervous systems affects many different biological processes through interaction with two major classes of acetylcholine receptors, nicotinic receptors and muscarinic acetylcholine. Muscarinic acetylcholine receptors (mAChRs) belong to the superfamily of G-protein coupled receptors that have seven transmembrane domains. There are five subtypes of mAChRs, called M1-5, and each is the product of a different gene. Each of these five subtypes exhibits unique pharmacological properties. The muscarinic receptors of acetylcholine are widely distributed in vertebrate organs and these receptors can mediate both inhibitory and excitatory actions. For example, in the smooth muscle found in the respiratory tract, the bladder and the gastrointestinal tract, contractile responses mediated by mAChRs M3. For a review, please see. { Brown 1989 247 / id} . Muscarinic receptor dysfunction of acetylcholine has been observed in a variety of different pathophysiological states. For example, in asthma and a chronic obstructive pulmonary disease (COPD), inflammatory conditions lead to the loss of the muscarinic auto-receptor function of acetylcholine M2 in the parasympathetic nerves that supply the pulmonary smooth muscle, causing an increase in the release of acetylcholine after l nerve stimulation. This mAChR dysfunction results in airway hyperreactivity as measured by increased stimulation of mAChRs M3. { Costello, Evans, et al. 1999 72 / id} . { Minette, Lammers, et al. 1989 248 / id} . Similarly, inflammation of the gastrointestinal tract in inflammatory bowel disease (IBD) results in hypermotility mediated by mAChRs M3. { Oprins, Meijer, et al. 2000 245 / id} . Incontinence due to hypercontractility of the bladder has also been shown to be mediated through the increased stimulation of mAChRs M3. { Hegde & Eglen 1999 251 / id} . In this way the identification of mAChR antagonists selective for the subtype may be useful as therapeutic in those mAChR mediated diseases. Regardless of the great evidence supporting the use of anti-muscarinic receptor therapy for the treatment of a variety of disease states, relatively few anti-muscarinic compounds are used in the clinical field. In this way, the need remains for novel compounds that are capable of causing blockage in mAChRs M3. Conditions associated with an increased stimulation of mAChRs M3, such as asthma, COPD, IBD and urinary incontinence could benefit from compounds that are inhibitors of mAChR binding.

BRIEF DESCRIPTION OF THE INVENTION This invention provides a method for the treatment of a disease mediated by the muscarinic acetylcholine receptor (mAChR), wherein the acetylcoane binds to an MAChR M3 and said method comprises the administration of an effective amount of a compound of formula (I ) or formula (II) [except the compound of formula (II) with R2 and R3 as 2-thiophene and R4 as -OC (0) CH3] or a pharmaceutically acceptable salt thereof. This invention also relates to a method for the inhibition of the binding of acetylcoane to its receptors in a mammal in need thereof comprising the administration to said mammal of an effective amount of a compound of formula (I) or formula ( II). The present invention also provides novel compounds of formula (I) or formula (II), and pharmaceutical compositions comprising a compound of formula (I) or formula (II), and a pharmaceutical carrier or diluent. Compounds of formula (I) or formula (II) useful in the present invention are represented by the structure: where: the indicated H atom is in the exo position; R1"represents an anion associated with the positive charge of the atom N. R1" may be, but is not limited to, chloride, bromide, iodide, sulfate, benzene sulfonate and toluene sulfonate; R2 and R3 is independently selected from the group consisting of straight or branched chain lower alkyl groups (preferably having 1 to 6 carbon atoms), cycloalkyl groups (having from 5 to 6 carbon atoms), cycloalkyl-alkyl ( having 6 to 10 carbon atoms), heterocycloalkyl (having 5 to 6 atoms) and N or O as the heteroatom, heterocycloalkyl-alkyl (having 6 to 10 carbon atoms) and N or O as the heteroatom , aryl, optionally substituted aryl, heteroaryl, and optionally substituted heteroaryl; R4 is selected from the group consisting of (CrC6) alkyl, (C3-C12) cycloalkyl, (C3-C7) heterocycloalkyl, (CrC6) alkyl (C3-C12) alkyl, (CrC6) -heterocycloalkyl (C3) alkyl -C7), aryl, heteroaryl, allkylaryl of (C-pCe), alkyl-heteroaryl of (C6), -OR5, -CH2OR5, -CH2OH, -CN, -FC3, -CH20 (CO) R6, -C02R7, -CH2NH2, -CH2N (R7) S02R5, -S02N (R7) (R8), - CON (R7) (R8), -CH2N (R8) CO (R6), -CH2N (R8) S02 (R6), -CH2N (R8) C02 (R5), - CH2N (R8) CONH (R7); R5 is selected from the group consisting of (Ci-C6) alkyl, alkyl (CrC6) -cycloalkyl (C3-Ci2), alkyl (C6) -heterocycloalkyl (C3-C7), alkyl-aryl (CrC6), alkyi -heteroaryl of (CrC6); R6 is selected from the group consisting of alkyl of (C- | -C6), cycloalkyl of (C3-C12), heterocycloalkyl of (C3-C7), alkyl (Ci-Ce) -cycloalkyl (C3-Ci2), alkyl ( Ci-C6) -heterocycloalkyl (C3-C7), aryl, heteroaryl, alkyl-aryl of (? -? -? ß), alkyl-heteroaryl of (CrC6); R7 and R8 are, independently, selected from the group consisting of H, alkyl of (CrC6), cycloalkyl of (C3-Ci2), heterocycloalkyl of (C3-C7), alkyl (CrC6) -cycloalkyl (C3-C12), alkyl (CrC6) -heterocycloalkyl (C3-C7), alkyl-aryl of (Ci-C6), and alkyl-heteroaryl of (CrC6). Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of formula (I) or formula (II) can also be formed with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali, alkaline earth, ammonium and quaternary ammonium cations. The following terms, as used herein, refer to: - "halo" - all halogens, ie chlorine, fluorine, bromine and iodine. "Ci, 10 alkyl" or "alkyl" - both straight or branched chain radicals of 1 to 10 carbon atoms, unless the length of the chain is otherwise limited, includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-buryl, sec-butyl, isobutyl, tere-butyl, n-pentyl and the like. "cycloalkyl" is used herein to refer to the cyclic radical, preferably from 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like. "alkenyl" is used herein in all occurrences to refer to the straight or branched chain radical of 2 to 10 carbon atoms, unless the chain length is limited thereto, including, but limited to ethenyl, 1 -propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. - "aryl" phenyl and naphthyl; - "heteroaryl" (as such or in any combination, such as "heteroaryloxy", or "heteroarylalkyl") a 5- to 10-membered aromatic ring system wherein one or more rings contains one or more heteroatoms selected from the group consisting of N, O or S such as, but not limited to, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole, thiazole, triadiazole, triazole, imidazole or benzimidazole. - "heterocyclic" (as such or in any combination, such as "heterocyclylalkyl") a saturated or partially unsaturated 4 to 10-membered ring system, wherein one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine or imidazolidine. In addition, the sulfur can optionally be oxidized to the sulfone or sulfoxide. "Arylalkyl" or "heteroarylalkyl" or "heterocyclic alkyl" is used herein to refer to C-O alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic radical, as defined herein, unless otherwise indicated otherwise. - "Sulfinyl" the S (O) oxide of the corresponding sulfide, the term "uncle" refers to the sulfide, and the term "sulfonyl" refers to the completely oxidized S (0) 2 radical. - "where two Ri radicals (or two Y radicals) together can form a 5 or 6 membered saturated or unsaturated ring" is used herein to refer to the formation of an aromatic ring system, such as naphthalene, or is a radical phenyl having a partially saturated or unsaturated 6-membered ring attached, such as C6 cycloalkeno, ie hexene, or a cycloalkenyl radical of C5, such as cyclopentene. Preferred compounds useful in the present invention include: (endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8- iodide azonia-bicyclo [3.2.1] octane; 3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionitrile; (endo) -8-methyl-3- (2,2,2-triphenyl-ethyl) -8-aza-bicyclo [3.2.1] octane; 3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide; 3 - ((Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-d-phenyl-propionic acid; Iodo (endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane; Bromide of (endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane; 3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propan-1-ol; N-benzyl-3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide; Iodo (endo) -3- (2-carbamoyl-2) 2-d-phenyl-ethyl) -8,8-d-methyl-8-azonia-bicyclo [3.2.1] octane; 1-benzyl-3- [3 - ((endo) -8-methyl-8-aza-b-cyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea; 1-Ethyl-3- [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea; N- [3 - ((endo) -8-methyl-8-aza-b] cyclo [3.2.1] oct-3-yl) -2,2-diphenol-propyl] -acetamide; N- [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -benzamide; 3 - ((endo) -8-methyI-8-aza-b-cyclo [3.2.1] oct-3-yl) -2,2-di-thiophen-2-yl-propionitrile; Iodide of (endo) -3- (2-c'iano-2,2-d¡-thiophen-2-yl-ethyl) -8,8-d'imethyl-8-azonia-bicyclo [3.2.1] octane; N- [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -benzenesulfonamide; [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-d-phenyl-propyl] -urea; N- [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenol-propyl] -methanesulfonamide; and Bromide of (endo) -3-. { 2,2-Diphenyl-3 - [(1-phenyl-methanoyl) -amino] -propyl} -8,8-dirnetil-8-azonia-bicclo [3.2.1] octane.

More preferred compounds useful in the present invention include: (endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo-iodide [3.2.1] octane; Iodo (endo) -3- (2-cyano-2,2-d-phenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane; Bromide of (endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane; Indole (endo) -3- (2-carbamoyl-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane; Iodo (endo) -3- (2-cyano-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane; and Bromide of (endo) -3-. { 2,2-Diphenyl-3 - [(1-phenyl-methanoyl) -amino] -propyl} -8,8-dimethyl-8-azone-bicyclo [3.2.1] octane.

Preparation methods Preparation The compounds of formula (I) and formula (II) can be obtained by applying synthetic procedures, some of which are illustrated in the subsequent schemes. The synthesis provided for these schemes can be applied for the production of compounds of formula (I) and (II) having a variety of different R1, R2, R3 and R4 which react, employing substituents that are suitably protected, for achieve compatibility with the reactions summarized here. Subsequent deprotection, in those cases, then results in compounds of the nature described in general. Although some schemes are shown with only compounds of formula (II), this is only for the purpose of being illustrative. The general preparation method is shown in scheme 1. The synthesis starts with compound 1. The reduction with lithium aluminum hydride (LAH) produces alcohol 2. Displacement with iodine provides 3. The coupling reaction with the derived anion of HCR2 (R3) (R4) then gives compound 4, which is easily converted to the ammonium salt 5.

SCHEME I A more specific preparation method leading to the compounds with formula (II) is summarized in scheme 2. The alkylation of ester HC (Ph) 2C02CH3 with 3 yields compound 6. Hydrolysis of 6 generates acid 7. The 1, 3-dicyclohexylcarbodiimide (DCC) mediates the condensation of the acid with the alcohol (R7) OH and then produces the ester 8. The condensation of acid 7 with the amine (R7) (R8) NH under suitable conditions of amide coupling is well known by those skilled in the art such as 1- (3-dimethylaminopropyl) -3-ethylcarbodumide hydrochloride (EDC.HCl) and 1-hydroxybenzotriazole hydrate (HOBt) provides the amide 9. The reduction of 6 generates alcohol 10. Reaction of 10 with acid chloride (R6) COCI or acid (R6) C02H produces ester 1. Alkylation of 10 with appropriate reagents such as (R5) Br then produces 12. The compounds with structure similar to 6, 7, 8, 9, 10, 11 and 12 are converted to the corresponding ammonium salts by reaction with reactants of appropriate reactions such as MeBr and Mel (not shown in the scheme). Appropriate protection and deprotection methods are used in some preparation methods.

SCHEME II A more specific preparation method leading to the compounds with formula (II) is summarized in scheme III. The alkylation of HC (Ph) 2CN with 3 provides the nitrile 13. The hydrolysis of 13 under basic conditions (for example, NaOH and H2O2) or acidic conditions (for example, H2S0) produces the amide 14. The reduction of 13 leads to amine 15 which is conveniently converted to amide 16, carbamide 17, sulfonamide 18 and urea 19. Condensation of 15 with aldehyde (R 8) CH (0) followed by reduction with NaBH (OAc) 3 yields amine. which is easily converted to amide 21, carbamide 22, urea 23 and sulfonamide 24. Compounds with structures similar to 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 are converted to the corresponding ammonium salts through the reaction with appropriate reaction reagents such as MeBr and Mel (not shown in the scheme). Appropriate protection and deprotection methods are used in some preparation methods.

SCHEME III A more specific preparation method carrying the compounds with formula (II) is summarized from scheme IV. Alkylation of 25 with (R5) Br yields 26. The reaction of 25 with Lawesson's reagent yields 27. Oxidation of 27 with S02CI2 and KN03 yields 28 which convert either to 29 or to sulfonamide 30. Compounds with structures similar to 26, 27, 29 and 30 are easily converted to the corresponding ammonium salts through the reaction with appropriate reaction reagents such as MeBr and Mel (not shown in the scheme). Appropriate protection and deprotection methods are used in some preparation methods.

SCHEME IV SYNTHETIC EXAMPLES The following examples are provided as an illustration of the present invention but do not limit it in any way; EXAMPLE 1 Iodide (Endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azonia-biciclof3.2.1 loctane To a solution of 2- (8 -methyl-8-azabicyclo [3.2.1] oct-3-yl) -1,1-dithiophen-2-yl-ethanol (prepared according to US2800482) (2.12 mg, 0.64 mmol) in 5 ml of methylene chloride and iodomethane (0.40 ml, 6.4 mmol), 50% aqueous potassium hydroxide (0.25 ml, 3.2 mmol) and tetrabutyl ammonium chloride (5 mg, 3 mol%) is added. The reaction mixture is heated to reflux for 5 days. Each day, 0.2 ml of iodomethane and 0.1 ml of additional potassium hydroxide are added. At the end, the reaction mixture is cooled to room temperature, diluted with methylene chloride and washed with water. The aqueous layer is extracted with methylene chloride and the combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is recrystallized from the methylene chloride / ethyl acetol to provide 109 mg of the title compound: LCMS (ES) m / z 362 (M) +.

EXAMPLE 2 3 - ((Endo) -8-aza-bicyclo3.2.11oct-3-yl) -2.2-diphenol-propionitrile 2a) Preparation of ((endo) -8-methyl-8-aza-bicyclo3.2.1oct-3-yl) -methanol A mixture of (endo) -3- (hydroxymethyl) -8-azabicyclo [3.2.1] 1, 1-dimethylethyl octane-8-carboxylate (0.50 g, 2.05 mmol) and LiAIH4 (6.16 mL, 1.0 M in THF, 6.16 mmol) is heated at 80 ° C with a microwave reactor for 60 minutes. The solution is then mixed with saturated Na 2 SO 9 solution. filter through celite and concentrate to yield the title compound (0.31 g, 97%): LCMS (ES) m / z 56 (M + H) +; 1 H-NMR (CDCl 3) d 1.28 (s, 1 H), 1.59 (m, 4 H), 1.90 (m, 1 H), 2.13 (m, 4 H), 2.32 (s, 3 H), 3.17 (s, 2 H) 3.59 (d, 2H). 2b) Preparation of (endo) -3-vodomethyl-8-methyl-8-azabicyclo3.2.noctane A solution of iodine (6.67 g, 25.8 mmol) and ((endo) -8-methyl-8-aza- bicyclo [3.2.1] oct-3-yl) -methanol (2.0 g, 12.9 mmol) in CH 2 Cl 2 (120 mL) is mixed with PPh 3 (on resin, 8.6 g, 3 mmol / g, 25.8 mmol). The resulting mixture is stirred for 17 hours, filtered and concentrated to yield the title compound (2.63 g, 77%): LCMS (ES) m / z 266 (M + H) +; 1 H-NMR (CDCl 3) d 2.05 (m, 4 H), 2.39 (m, 3 H), 2.79 (d, 3 H), 2.98 (m, 2 H), 3.45 (d, 2 H), 3.81 (s, 2 H). 2c) Preparation of 3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.11oct-3-yl) -2,2-diphenyl-propionitrile A solution of 3 - ((endo) -3-iodomethyl-8-methyl-8-aza-bicyclo [3.2.1] octane (1.06 g, 4.0 mmol) and Ph2CHCN (2.32 g, 12.0 mmol) in DMF (20 mL) is mixed with NaH (0.288 g, 12.0 mmol) The resulting mixture is stirred at room temperature for 60 minutes The filtration and purification by reverse phase HPLC (Gilson) then yields the title compound (1.16 g, 93%): LC S (ES) m / z 331 (M + H) +; 1 H-NMR (CDCl 3) d 1.64 (m, 2 H), 2.14 (m, 1 H), 2.26 (m, 2 H), 2.34 (m, 2 H), 2.52 (m, 2H), 2.75 (m, 5H), 3.83 (s, 2H), 7.39 (d, 10H). fEnd) -8-methyl-3- (2,2,2-triphenyl-etl) -8-aza-bicyclo3.2.noctane A solution of triphenyl methane (0.276 g, 1.13 mmol) in THF (0.5 ml) it was mixed with n-BuLi (0.706 ml, 1.6 M in Hexane, 1.13 mmol). The solution was stirred for 10 minutes and added by a solution of (endo) -3-iodomethyl-8-methyl-8-aza-bicyclo [3.2.1] octane (100 mg, 0.377 mmol) in DMF (1.0 ml). . The mixture is stirred at room temperature for 60 minutes, mixed with H20 (0.1 ml), concentrated and filtered. Purification through reverse phase HPLC (Gilson) then yields the title compound (23.8 mg, 17%): LCMS (ES) m / z 382 (M + H) +; 1 H-NMR (CDCl 3) d 1.07 (d, 2 H) 2.12 (m, 1 H), 2.22 (m, 4 H), 2.31 (m, 2 H), 2.65 (d, 3 H), 2.97 (d, 2 H), 3.63 (s, 2H), 7.21 (m, 3H), 7.30 (d, 12H).

EXAMPLE 4 3- (fEnd) -8-methyl-8-aza-bicyclo3.2.noct-3-yl) -2,2-diphenyl-propionamide A solution of 3 - ((endo) -8-methyl-8-aza- bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionitrile (53 mg, 0.16 mmol) in CH2Cl2 (0.25 mL) is mixed with H2SO4 (0.28 mL, 96%) and stirred at 40 ° C for 30 hours. The mixture is then poured into yarn, neutralized with NH3H20, extracted with EtOAc and concentrated. The resulting residue is dissolved in DMSO and filtered. Purification by reverse phase HPLC (Gilson) gives the title compound (17.2 mg, 30%): MS (ES) m / z 347 (M + H) +; H-NMR (CDCl 3) d 1.31 (d, 2 H), 1.98 (m, 1 H), 2.28 (m, 4 H), 2.39 (m, 2 H), 2.67 (d, 3 H), 2.79 (d, 2 H), 3.66 (s, 2H), 5.82 (s, br, 1 H), 6.88 (s, br, 1 H), 7.37 (m, 10H).

EXAMPLE 5 3 - ((Endo-8-methyl-8-aza-bicichlor3.2.1loct-3-in-2,2-diphenyl-propionic acid A solution of 2 - [(3-endo) -8-methyl-8 -azabicyclo [3.2.1] oct-3-yl] -1,1-diphenylethanol (100 mg, 1.56 mmol) in HCOOH (0.25 ml) is added rapidly through H2SO4 (2.73 ml, 90%) at 0 ° C The reaction bottle is immediately capped and stored in a refrigerator at -20 ° C for 7 days.The solution is poured onto ice, neutralized with NH3H20, extracted with EtOAc and concentrated.The resulting residue is dissolved in DMSO and filtered The purification through a reverse phase HPLC (Gilson) then yields the title compound (52 mg, 48%): LCMS (ES) m / z 350 (M + H) +; NMR (eOD) d 1.39 (d, 2H), 1.86 (m, 1H), 1.97 (m, 2H), 2.30 (m, 4H), 2.69 (s, 3H), 2.84 (d, 2H), 3.69 (s) , 2H), 7.28 (m, 2H), 7.36 (m, 8H).

EXAMPLE 6 Bromide of (endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-biciclof3.2.1 loctane A solution of 3 - ((endo) -8- methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionitrile (310 mg, 0.938 mmol) in acetone (6.0 ml) is mixed with MeBr (4.69 ml, 2.0 M in f-BuOMe, 9.38 mmol). The resulting mixture is stirred at room temperature for 60 minutes and filtered. The solid is washed with acetone (2-3 mL) to yield the title compound (333 mg, 83%): LCMS (ES) miz 345 (M) +; H-NMR (MeOD) d 1.82 (d, 2H), 2.17 (m, 1H), 2.35 (m, 2H), 2.49 (m, 4H), 3.01 (d, 2H), 3.07 (s, 3H), 3.10 (s, 3H), 3.79 (s, 2H), 7.36 (m, 2H), 7.43 (m, 4H), 7.49 (m, 4H).

EXAMPLE 7 Iodide of (endo) -3- (2-cyano-2,2-d-phenyl-etl) -8,8-dimethyl-8-azonia-biciclof3.2.11octane A solution of 3 - ((endo ) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionitrile (26.5 mg, 0.080 mmol) in CH2Cl2 (0.5 mL) and MeCN (0.5 mL) were mixture with (0.125 ml, 2.00 mmol). The resulting mixture is stirred at room temperature for 3 hours, diluted with DMSO (0.3 ml) and concentrated. Purification through reverse phase HPLC (Gilson) then yields the title compound (22.9 mg, 60%): LCMS (ES) m / z 345 (M) +; 1 H-NMR (CDCl 3) d 1.83 (d, 2 H), 2.17 (m, 1 H), 2.35 (m, 2 H), 2.49 (m, 4 H), 3.01 (d, 2 H), 3.07 (s, 3 H), 3.10 (s, 3H), 3.79 (s, 2H), 7.36 (m, 2H), 7.43 (m, 4H), 7.49 (m, 4H).

EXAMPLE 8 3 - ((Endo) -8-methyl-8-aza-bichloro3.2.noct-3-yl) -2,2-diphenol-propan-1- oi A mixture of 3 - (endo ) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionic (42.5 mg, 0.122 mmol) and LiAIH4 (0.488 mL, 1.0 M in THF, 0.488 mmol ) is heated with a microwave reactor at 100 ° C for 1 hour. It is diluted with saturated Na 2 SO 4 solution, filtered through celite and concentrated. The resulting residue is dissolved in DMSO and filtered. Purification through reverse phase HPLC (Gilson) then yields the title compound (29.1 mg, 71%): LCMS (ES) m / z 336 (M + H) +; 1 H-NMR (CDCl 3) d 1.40 (d, 2 H), 1.92 (m, 1 H), 2.29 (m, 6 H), 2.59 (m, 2 H), 2.68 (d, 3 H), 3.72 (s, 2 H), 4.16 (s, 2H), 7.13 (m, 3H), 7.30 (m, 7H).

EXAMPLE 9 A-Benzyl-3-f (fendo) -8-methyl-8-aza-bicichlor3.2.11oct-3-yl) -2,2-diphenyl-propionamide A solution of 3 - ((endo) -8-methyl) acid -8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionic acid (82.0 mg, 0.235 mmol) in CH2Cl2 (3.0 ml) is mixed with PhCH2NH2 (28.2 μ ?, 0.258 mmol) , EDC (49.5 mg, 0.258 mmol), HOBt (3.2 mg, 0.024 mmol) and (CH3CH2) 3 N (0.232 mL, 1.65 mmol). The mixture is stirred at room temperature for 60 hours and concentrated. The resulting residue is dissolved in DMSO and filtered. Purification by reverse phase HPLC (Gilson) then yields the title compound (29.8 mg, 30%): LCMS (ES) m / z 439 (M + H) +; H-NMR (CDCl 3) d 1.34 (d, 2H), 1.96 (m, 1 H), 2.23 (m, 2H), 2.38 (m, 4H), 2.63 (d, 3H), 2.83 (d, 2H), 3.66 (s, 2H), 4.41 (d, 2H), 6.93 (m, 2H), 7.22 (m, 3H), 7.38 (m, 0H). 7 EXAMPLE 10 Iodide of (endo) -3- (2-carbamo [-] - 212-diphenyl) -ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1-octane The title compound is prepared from - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide by following the procedure of Example 7 (33% yield): LCMS ( ES) m / z 363 (M) +; 1 H-NMR (CDCl 3) d 1.49 (d, 2 H), 1.95 (m, 1 H), 2.25 (m, 2 H), 2.42 (m, 4 H), 2.84 (d, 2 H), 3.17 (s, 3 H) , 3.23 (s, 3H), 3.93 (s, 2H), 5.65 (s, H), 5.91 (s, 1H), 7.39 (m, 10H). 1-Benzyl-3-f3 - ((endo) -8-methyl-8-aza-bicycloF3.2.1loct-3-yl) -2.2-diphenyl-propyl] -urea 11 a) 3 - ((endo-8-methyl-8-aza-bicichlor3.2.1loct-3-yl) -2.2-diphenyl-propylamine A solution of 3 - ((endo) -8-methyl-8- aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionitrile (250 mg, 0.758 mmol) in THF (2.5 mL) is mixed with BH3 (2.53 mL, 1.5 M in THF, 3.79 mmol) at 0 ° C. The mixture is stirred at room temperature for 20 hours and diluted with H20 (.0 ml), then the solution is mixed with K2CO3 (0.1 g) and stirred at room temperature for 1 hour. The organic layers are separated and the aqueous part is extracted with EtOAc (2 x 30 mL), the organic layers are combined, dried over Na 2 SO 4 and concentrated, purification by reverse phase HPLC (Gilson) yields the title compound. (159 mg, 63%): LCMS (ES) m / z 335 (M + H) +; 1 H-RN (MeOD) d 1.35 (d, 2H), 2.01 (m, 3H), 2.34 (s, 4H) , 2.55 s, 2H), 2.68 (s, 3H), 3.73 (m, 5H), 7.26 (m, 4H), 7.33 (m, 2H), 7.43 (m, 4H). 11 b) 1-Benzyl-3-r3 - ((endo) -8-methyl-8-aza-bicic [or3.2.11oct-3-yl] -2,2-diphenylpropyl-urea A solution of 3- ((Endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropylamine (50.0 mg, 0.149 mmol) in CH2Cl2 (2.0 mL) is mixed with PhCH2NCO (20.4 μ [_, 0.64 mmol) and (CH 3 CH 2) 3 N (62.8 μ? _, 0447 mmol). The resulting mixture is stirred at room temperature for 1 hour and concentrated. Purification by reverse phase HPLC (Gilson) then yields the title compound (13.0 mg, 19%): LCMS (ES) m / z 468 (M + H) +; 1 H-NMR (MeOD) d 1.24 (d, 2 H), 1.94 (m, 3 H), 2.25 (m, 4 H), 2.49 (d, 2 H), 2.67 (s, 3 H), 3.62 (s, 2 H), 3.97 (s, 2H), 4.23 (s, 2H), 7.22 (m, 6H), 7.33 (m, 4H).

EXAMPLE 12 1-Ethyl-3-r3 - ((endo) -8-methyl-8-aza-bicichlor3.2.noct-3-yl) -2.2-diphenyl-propyl-urea The title compound is prepared from 3- ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-ii) -2,2-diphenyl-propylamine and CH3CH2NCO following the procedure mentioned in example 11 (45% yield) ): LCMS (ES) m / z 406 (M + H) +; 1 H-NMR (MeOD) d 1.03 (t, 3 H), 1.33 (d, 2 H), 1.94 (m, 3 H), 2.25 (m, 4H), 2.55 (d, 2H), 2.67 (s, 3H), 3.07 (q, 2H), 3.68 (s, 2H), 3.94 (s, 2H), 7.24 (m, 6H), 7.34 ( m, 4H).

EXAMPLE 13 /V-r3-((Endo)-8-metil-8-aza-biciclor3.2.noct-3-il)-2.2-difenil-propin- benzamida A solution of 3 - ((endo) -8-metii-8-aza-b-cyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propylamine (33.4 mg, 0.10 mmol) in CH2Cl2 ( 0.5 mL) is mixed with AC2O (18.9 μ ?, 0.20 mmol) and pyridine (16.2 μ ?, 0.20 mmol). The mixture is stirred at room temperature for 1 hour and concentrated. Purification through reverse phase HPLC (Gilson) then gives the title compound (10.7 mg, 29%): LCMS (ES) m / z 377 (M + H) +; H + NMR (MeOD) d 1.26 (d, 2H), 1.82 (s, 3H), 1.96 (m, 3H), 2.26 (s, 4H), 2.53 (d, 2H), 2.67 (s, 3H), 3.66 (s, 2H), 4.00 (s, 2H), 7.24 (m, 6H), 7.33 (m, 4H).

EXAMPLE 14 A / - [3 - ((EndoV8-methyl-8-aza-bicichlor3.2.11oct-3-yl) -2,2-diphenyl-propin-benzamide The title compound is prepared from 3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-d-phenyl-propylamine and (PhCO) 20 following the procedure described in example 13 (yield 8%): LCMS (ES) m / z 439 (M + H) +; 1 H-NMR (MeOD) d 1.28 (d, 2H), 2.00 (m, 3H), 2.24 (s, 4H), 2.59 (d, 2H), 2.67 (s, 3H), 3.65 (s, 2H), 4.21 (s, 2H), 7.31 (m, 6H), 7.39 (m, 6H), 7.50 (m, 3H).

EXAMPLE 15 3 - ((Endo) -8-methyl-8-aza-bicyclo3.2.noct-3-H) -2,2-di-thiophen-2-yl-propionitrile The title compound is prepared from (endo) ) -3-iodomethyl-8-methyl-8-aza-bicyclo [3.2.1] octane and 2,2-di-thiophen-2-yl-acetonitrile following the procedure described in example 2C (34% yield) ): LCMS (ES) m / z 343 (M + H) +; 1 H-NMR (CDCl 3) d 1.79 (m, 2 H), 2.21 (m, 2 H), 2.33 (m, 2 H), 2.62 (m, 2 H), 2.73 (m, 4 H), 3.80 (m, 2 H), 4.35 (s, 2H), 7.02 (m, 2H), 7.23 (m, 2H), 7.37 (m, 2H).

EXAMPLE 16 Iodo (Endo) -3- (2-cyano-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azoniabicyclo3.2.11octane The title compound is prepared from 3- ( (endo) -8-methyl-aza-bicyclo [3.2.1] oct-3-yl) -2,2-di-thiophen-2-yl-propionitrile following the procedure described in Example 7 ( %): LC S (ES) m / z 345 () +; 1 H-NMR (CDCl 3) d 1.82 (d, 2 H), 2.35 (m, 2 H), 2.23 (m, 3 H), 2.58 (m, 4 H), 2.82 (m, 2 H), 3.37 (s, 6 H), 4.25 (s, 2H), 7.02 (m, 2H), 7.24 (m, 2H), 7.36 (m, 2H).

EXAMPLE 17 A / -r3 - ((Endo) -8-methyl-8-aza-bichloro3.2.11oct-3-yl) -2,2-diphenii-propyl-1-benzenesulfonamide A solution of 3 - ((endo) -8-methyl) -8-aza-bicyclo- [3.2.1] oct-3-yl) -2,2-diphenylpropylamine (67.0 mg, 0.20 mmol) in CH2Cl2 (2.0 ml) is mixed with PhS02CI (28.2 μ? _, 0.22 mmol) and (CH 3 CH 2) 3 N (84.3 μ ?, 0.60 mmol). The resulting mixture is stirred at room temperature for 1 hour and concentrated. Purification by reverse phase HPLC (Gilson) then yields the title compound (51.5 mg, 54%): LCMS (ES) m / z 475 (M + H) +; H NMR (MeOD) d 1.39 (d, 2H), 2.01 (m, 3H), 2.30 (s, 4H), 2.69 (s, 5H), 3.60 (s, 2H), 3.68 (s, 2H), 7.12 ( m, 4H), 7.27 (m, 6H), 7.55 (m, 2H), 7.63 (m, 1 H), 7.78 (m, 2H).

EXAMPLE 18 r3 - ((endo) -8-methy1-8-aza-b-cyclo3.2.noct-3-n-2,2-diphenyl-propyl-urea To a solution of 3 - ((endo) -8- methyl-8-aza-bicyc [3.2.1] oct-3-yl) -2,2-diphenyl-propylamine (50.0 mg, 0.149 mmol) in CH2Cl2 (4.0 mL), CIS02NCO (31.2 μ ?, 0.358 mmol) was The mixture is stirred at room temperature for 2 days and concentrated, purification by reverse phase HPLC (Gilson) then yields the title compound (21.6 mg, 38%) LCMS (ES) m / z 378 (M + H); 1H NMR (MeOD) d 1.33 (d, 2H), 2.01 (m, 3H), 2.29 (s, 4H), 2.57 (m, 2H), 2.68 (s, 3H), 3.69 (s) , 2H), 4.01 (s, 2H), 7.25 (m, 6H), 7.34 (m, 4H).

EXAMPLE 19 N-r3 - ((endo) -8-methyl-8-aza-bicyclo3.2.11oct-3-yl) -2,2-diphenyl-propyl-1-methanesulfonamide The title compound is prepared from 3 - ((endo ) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propylamine and MeS02CI following the procedure in example 17 (28% yield). LCM (ES) m / z 413 (M + H) +. 1 H NMR (MeOD) d 1.39 (d, 2 H), 1.97 (m, 3 H), 2.30 (s, 4 H), 2.68 (s, 3 H), 2.76 (s, 3 H), 2.76 (s, 3 H), 3.68 ( s, 2H), 3.84 (s, 2H), 7.23 (s, 6H), 7.33 (s, 4H).

EXAMPLE 20 Bromide of (endo) -3-. { 2,2-diphenyl-3-r (1-phenyl-methanoyl) -aminol-propyl} -8,8-d-methyl-8-azonia-b¡c¡clof3.2.11octane A solution of N- [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct- 3-yl) -2,2-diphenyl-propyl] -benzamide (29 mg, 0.0683 mmol) in CH2Cl2 (0.5 mL) and acetone (0.5 mL) is mixed with MeBr (0.342 mL, 2.0 M in t-butyl). methyl ether, 0.683 mmol). The resulting mixture is stirred at room temperature for 3 hours and concentrated. Purification by reverse phase HPLC (Gilson) then affords the title compound (19.6 mg, 64%): LCM (ES) m / z 453 (M) + 1 H NMR (MeOD) d 1.20 (d, 2H) , 2.32 (m, 7H), 2.65 (d, 2H), 2.98 (s, 3H), 3.02 (s, 3H), 3.60 (s, 2H), 4.22 (s, 2H), 7.30 (m, 6H), 7.39 (m, 6H), 7.50 (s, 3H).

BIOLOGICAL EXAMPLES The inhibitory effects of the compounds in the mAChR M3 of the present invention are determined following the in vitro and in vivo test: Analysis of inhibition of receptor activation through calcium mobilization: The stimulation of mAChRs expressed in CHO cells is analyzed by monitoring the mobilization of calcium activated by receptor as previously described10. CHO cells stably express mAChRs M3 and place in 96-well black-wall / clear-bottom plates. After 18 to 24 hours, the medium is aspirated and replaced with 100 μ? of loading medium (EMEM with Earl's salts, BSA grade 0.1% RIA (Sigma, St. Louis MO), and 4 [mu] of Fluo-3-acetoxymethyl ester which is a fluorescent indicator dye (Fluo-3 AM, Probes Molecular, Eugene, OR) and incubated 1 hour at 37 ° C. The dye-containing media is then aspirated, replaced with fresh medium (without Fluo-3 AM), and the cells are incubated for 10 minutes at 37 ° C. The cells are then washed 3 times and incubated for 10 minutes at 37 ° C in assay pH buffer 00 μ (0.1% gelatin (Sigma), 120 mM NaCl, 4.6 mM KCI, 1 mM KH2 P04, 25 mM NaH C03, 1.0 mM CaCl2, 1.1 mM MgCI2l 1 mM glucose, 20 mM HEPES (pH 7.4)) 50 μm of compound (1? 10"11-1? 10.5 M end in the assay) are added and the plates are incubated for 10 minutes at 37 ° C. The plates are then placed in a fluorescent light intensity plate reader (FLIPR, Molecular Probes) where cells loaded with dye are exposed to excitation light n (488 nm) of a 6-watt argon laser. The cells are cultured by adding 50 μ? of acetylcholine (0.1-10 nM final), prepared in pH buffer containing 0.1% BSA, at a rate of 50 μ? / second. Calcium mobilization, monitored as the change in cytosolic calcium concentration, is measured as the change in an emission intensity of 566 nm. The change in emission intensity is directly related to cytosolic calcium levels11. The fluorescence emitted from all 96 wells is measured simultaneously using a cooled CCD camera. The data points are collected every second. These data are then plotted and analyzed using a GraphPad PRISM software.

Methacholine-induced bronchoconstriction Respiratory sensitivity to methacholine is determined in BalbC mice without restrictions, awake (n = 6 each group). Barometric plethysmography is used to measure the increased pause (Penh), a measure without unity that has been shown to correlate with changes in airway resistance that occur during the bronchial challenge with methacholine12. The mice are pretreated with 50 μ? of compound (0.003-10 g / mouse) in 50 μ? of vehicle (10% DMSO) intranasally, and then placed in the plethysmography chamber. Once in the chamber, the mice are allowed to equilibrate for 10 minutes before taking the baseline for the measurement for 5 minutes. The mice are then challenged with a methacholine aerosol (10 mg / ml) for 2 minutes. Penh is recorded continuously for 7 minutes starting at the inception of the methacholine aerosol, and continuing for 5 minutes afterwards. The data for each mouse is analyzed and plotted using a GraphPad PRISM software.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound having structure I or II as indicated below except the compound of formula (II) with R2 and R3 as 2-thiophene and R4 as -OC (0) CH3: where: the indicated H atom is in the exo position; R1"represents an anion associated with the positive charge of the atom N. R1" may be, but is not limited to, chloride, bromide, iodide, sulfate, benzene sulfonate and toluene sulfonate; R2 and R3 is independently selected from the group consisting of straight or branched chain lower alkyl groups (preferably having 1 to 6 carbon atoms), cycloalkyl groups (having from 5 to 6 carbon atoms), cycloalicylate-alkyl ( having 6 to 10 carbon atoms), heterocycloalkyl (having 5 to 6 atoms) and N or O as the heteroatom, heterocycloalkyl-alkyl (having 6 to 10 carbon atoms) and N or O as the heteroatom , aryl, optionally substituted aryl, heteroaryl, and optionally substituted heteroaryl; R4 is selected from the group consisting of (CrC6) alkyl, (C3-C12) cycloalkyl, (C3-C7) heterocycloalkyl, (Ci-C6) alkyl-cycloalkyl (C3-Ci2), (C6) alkyl- (C3-C7) -heterocycloalkyl, aryl, heteroaryl, (Ci-C6) -alkylaryl, -alkyl-heteroaryl of (CrC6), -OR5, -CH2OR5, -CH2OH, -CN, -CF3, -CH20 (CO) R6, - C02R7, -CH2NH2, -CH2N (R7) S02R5, -S02N (R7) (R8), -CON (R7) (R8), -CH2N (R8) CO (R6), -CH2N (R8) S02 (R6), -CH2N (R8) C02 (R5), CH2N (R8) CONH (R7); R5 is selected from the group consisting of (Ci-C6) alkyl, (C6) alkyl-cycloalkyl (C3-Ci2), alkyl (CrCei-heterocycloalkyl (C3-C), alkyl-aryl of (CrC6), alkyl- heteroaryl (C Ce); R6 is selected from the group consisting of (CrC6) alkyl, (C3-C2) cycloalkyl, (C3-C7) heterocycloalkyl, (Ci-C6) alkyl-cycloalkyl (C3-C) 2), alkyl (CrC6) -heterocycloalkyl (C3-C7), aryl, heteroaryl, alkyl-aryl of (CrC6), alkyl-heteroaryl of (C Ce); R7 and R8 are independently selected from the group consisting of H , alkyl (CrC6), cycloalkyl (C3-C2), heterocycloalkyl (C3-C7), alkyl (Ci-C6) -cycloalkyl (C3-C12), alkyl (CrC6) -heterocycloalkyl (C3-C7), alkyl-aryl of (Ci-C6), and alkyl-heteroaryl of (CrC6)

2. The compound according to claim 1, further characterized by having the rear structure I:

3. The compound according to claim 1, further characterized in that it is selected from the group consisting of: (endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl) -8 iodide , 8-dimethyl-8-azonia-bicyclo [3.2.1] octane; 3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-d-phenylpropionitrile; (endo) -8-methyl-3- (2,2,2-triphenyl-etl) -8-aza-bicyclo [3.2.1] octane; 3- ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenol-propionamide; 3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionic acid; iodide of (endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane; (endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane bromide; 3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propan-1-ol; N-benzyl-3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide; iodide of (endo) -3- (2-carbamoyl-2,2-d-phenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane; 1-Benzyl-3- [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea; 1-Ethyl-3- [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea; N- [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -acetamide; N- [3 - ((endo) -8-methyI-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -benzamide; 3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-di-thiophen-2-yl-propionitrile; iodide of (endo) -3- (2-cyano-2,2-di-thiophen-2-yl-ethyl) -8,8-dimethyl-8-azone-bicyclo [3.2.1] octane; N- [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-d-phenyl-propyl] -benzenesulfonamide; [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea; N- [3 - ((endo) -8-methyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -methanesulfonamide; and (endo) -3- bromide. { 2,2-D-phenyl-3 - [(1-phenyllomethano) -amino] -propyl} -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane.

4. The compound according to claim 3, further characterized in that it is selected from the group consisting of: (endo) -3- (2-methoxy-2,2-di-thiophen-2-yl-ethyl iodide) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane; iodide of (endo) -3- (2-cyano-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicido [3.2.1] octane; (endo) -3- (2-cyano-2,2-diphenyl-etiI) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane bromide; iodide of (endo) -3- (2-carbamoyl-2,2-diphenyl-ethyl) -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane; iodide of (endo) -3- (2-cyano-2,2-di-thiophen-2-yl-ethyl) -8,8-d-methyl-8-azonia-bicyclo [3.2.1] octane; and (endo) -3- bromide. { 2,2-Diphenyl-3 - [(1-phenyl-methanoyl) -amino] -propyl} -8,8-dimethyl-8-azonia-bicyclo [3.2.1] octane.

5. - A pharmaceutical composition for the treatment of diseases mediated by the muscarinic acetylcholine receptor comprising a compound defined in claim 1 and a pharmaceutically acceptable carrier thereof.

6. The use of a compound defined in claim 1, for the preparation of a medicament for inhibiting the binding of acetylcholine to its receptors in a mammal.

7. The use of a compound as defined in claim 1, for the preparation of a medicament for treating a disease mediated by the muscarinic acetylcholine receptor, wherein the acetylcholine binds to said receptor.

8. - The use as claimed in claim 7, wherein the disease is selected from the group consisting of chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema and allergic rhinitis.

9. The use as claimed in claim 7, wherein said medicament is formulated to be administrable via inhalation through the mouth or nose.

10. The use as claimed in claim 7, wherein said medicament is administrable via a medicament dispenser selected from a dry powder inhaler of the reservoir, a multiple dose dry powder inhaler or a metered dose inhaler.

11. The use as claimed in claim 7, wherein the medicament is administrable to a human and has a duration of action of 12 hours or more for a dose of 1 mg.

12. The use as claimed in claim 11, wherein the compound has a duration of action of 24 hours or more.

13. The use as claimed in claim 12, wherein the compound has a duration of action of 36 hours or more.